Field of the Disclosure
The present disclosure relates generally to pharmaceutical compositions, and more particularly, to oral transmucosal pharmaceutical compositions including testosterone synergistically combined with an aromatase inhibitor (AI) for testosterone deficiency and to maintain estradiol within normal physiologic levels.
Background Information
Testosterone is the androgenic hormone primarily responsible for normal growth and development of male sex and reproductive organs, including the penis, testicles, scrotum, prostate, and seminal vesicles. Testosterone facilitates the development of secondary male sex characteristics such as musculature, bone mass, fat distribution, hair patterns, laryngeal enlargement, and vocal cord thickening, among others. Additionally, normal testosterone levels maintain energy level, healthy mood, fertility, and sexual desire.
The production of testosterone by the testes is regulated by a complex chain of signals that begins in the brain, mediated by the hypothalamic-pituitary-gonadal axis. The hypothalamus secretes gonadotropin-releasing hormone (GnRH) to the pituitary gland in pulses (bursts) which triggers the secretion of luteinizing hormone (LH) from the pituitary gland. Luteinizing hormone stimulates the Leydig cells of the testes to produce testosterone. Normally, the testes produce approximately 4 mg to 7 mg of testosterone per day.
Generally speaking, testosterone production declines naturally with age. In addition, low testosterone, or testosterone deficiency (TD), may result from disease or damage to the hypothalamus, pituitary gland or testicles that inhibits hormone secretion and testosterone production, and is also known as hypogonadism. Depending on age, insufficient testosterone production can lead to abnormalities in muscle and bone development, underdeveloped genitalia and diminished virility.
Currently, the most common treatment for symptomatic male testosterone deficiency is testosterone therapy with various transdermal, oral, buccal, and injectable delivery methods. These methods typically involve very high doses of testosterone. The main purpose of the testosterone replacement therapy is to achieve normal range of testosterone serum levels.
Oral therapy of testosterone lacks effectiveness because testosterone is metabolized extensively during the first passage of the liver before reaching the systemic blood circulation (e.g., the first-pass effect). Intramuscular injections of testosterone esters are widely used, but local pain, tolerability, and the unphysiologically high levels of testosterone in the body during the first days/weeks after injection are severe drawbacks to this form of treatment. Local pain is attributed to the large volumes of testosterone injected and the required help of health care professionals makes injections inconvenient and expensive. These same drawbacks also apply to implanted pellets.
Transdermal administration (e.g., patches, gels, etc.) has the benefit that the first-pass effect is avoided and the treatment is not painful. Unfortunately, transdermal compositions, excluding patches, currently prescribed for hypogonadal men include from 40 mg to 120 mg daily doses of which only a low percentage is absorbed through the skin. Another drawback is that a large part of the testosterone remains on the skin with the potential risk of being transferred to another person when direct skin-to-skin contact is made. Additionally, the non-absorbed portion of testosterone is lost to the surrounding environment making these formulations non-environmentally-friendly. Additionally, a common side effect of transdermal compositions is local skin irritation. This is likely due to the very high ethanol content of such formulations.
Oral transmucosal delivery is a particularly advantageous delivery route. One of the advantages of oral transmucosal delivery is that it is a non-invasive drug delivery method. It promotes better patient compliance and involves lower costs than invasive procedures such as injection and implantation. Oral transmucosal delivery also results in much shorter onset time (e.g., the time from administration to therapeutic effect) than oral delivery does and may be easily self-administered. Oral transmucosal administration involves the patient holding the composition in the oral cavity while the API dissolves in the available fluid, diffuses through the mucosa lining of the mouth, and enters the bloodstream bypassing the gastrointestinal tract as well as hepatic metabolism.
Recently, research studies have demonstrated that aromatase inhibitors (AIs) as APIs may be used to treat low testosterone levels in men. AIs work by binding to the aromatase and inhibiting this enzyme that converts testosterone into estrogen. Estradiol serves as a major mediator of sex steroid-gonadotropin feedback; hence, high estradiol levels could contribute to low testosterone production through inhibition of LH. Meanwhile, high estradiol levels can also exist independently of testosterone levels. AIs effectively inhibit or block conversion of testosterone into estrogen which leads to increased LH and follicle-stimulating hormone (FSH) release from the pituitary. Increased LH and FSH results in a subsequent increase in testicular stimulation and serum testosterone levels without the increase in estrogen levels, and thus could limit the likelihood of undesirable effects such as gynecomastia. However, there are no AI products on the market that are indicated for treatment of testosterone deficiency while maintaining physiologic levels of estradiol.